Oxabicyclo[3.1.0]hexan-2-ones

ABSTRACT

Novel compounds of the formula I   &lt;IMAGE&gt; (I)  in which each of Y1 and Y2 independently represents a fluorine, chlorine or bromine atom and each of R1 and R2 independently represents a hydrogen atom or an alkyl group having up to 10 carbon atoms, or R1 and R2 together represent an alkylene group having from 2 to 5 carbon atoms, may be converted by the action of base into the corresponding dihalovinylcyclopropane carboxylic acids which are intermediates for preparing known pyrethroid insecticides.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel oxabicyclo[3.1.0]hexan-2-ones, a processfor their preparation and their use in a process for the preparation ofdihalovinylcyclopropanecarboxylic acids.

2. Description of the Prior Art

Synthetic pyrethroid insecticides are esters which consist of an acidportion and an alcohol portion. In one group of pyrethroids disclosed inU.S. Pat. No. 4,024,163, the acid portion is derived from a2,2-dihalovinylcyclopropanecarboxylic acid. Such an acid exists in theform of geometric isomers, in which the 2,2-dihalovinyl and the carboxylgroups are cis or trans to each other. Synthetic pyrethroids in whichthis acid portion is in the cis form are, in general, more active asinsecticides than the corresponding trans compounds, and a great deal ofresearch has been directed towards the preparation of cis2,2-dihalovinylcyclopropanecarboxylic acids.

The applicant has now found a group of dihalolactones which areconvenient to prepare and which can be converted readily into thedesired cis dihalovinylcyclopropanecarboxylic acids.

SUMMARY OF THE INVENTION

The present invention is directed to novel compounds of the formula I##STR2## in which each of Y¹ and Y² independently represents a fluorine,chlorine or bromine atom and each of R¹ and R² independently representsa hydrogen atom or an alkyl group having up to 10 carbon atoms, or R¹and R² together represent an alkylene group having from 2 to 5 carbonatoms.

The substituents Y¹ and Y² may be the same or different, but arepreferably the same. Preferably, Y¹ and Y² both represent bromine atomsor, especially, chlorine atoms.

R¹ and R² may be the same or different, but are preferably the same.Preferably each of R¹ and R² represents an alkyl group having 1 to 4,especially 1 or 2, carbon atoms. Most preferably, both R¹ and R²represent methyl groups.

Thus an especially preferred compound of the general formula I is thecompound in which both of Y¹ and Y² represent chlorine atoms, and bothof R¹ and R² represent methyl groups.

Compounds of the general formula I exist in the form of optical andgeometric isomers. Thus the compounds may have the R or the Sconfiguration about the cyclopropane carbon atom bearing the --CO₂ --group, and the CHY¹ Y² group may be endo or exo to the cyclopropanering. Further possibilities for isomerism exist depending on themeanings of Y¹, Y², R¹ and R². The invention should be understood toinclude all individual isomers as well as mixtures thereof.

The invention also provides a process for the preparation of a compoundof the general formula I, which comprises either reducing a compound ofthe formula II ##STR3## in which Y¹, Y², R¹ and R² have the meaningsgiven for the formula I, Y³ represents a chlorine or bromine atom, and Zrepresents a hydroxy group and either X represents a hydrogen atom and Wrepresents a hydroxy group or X and W together represent an oxygen atom,or Z and X together represent an oxygen atom and W represents a hydroxygroup, with a selective metal salt reducing agent, or dehydrating acompound of the general formula II, in which Y¹, Y², R¹ and R² have themeanings given for the general formula I, Y³ and X both representhydrogen atoms, and W and Z both represent hydroxy groups, using anysuitable dehydrating agent.

If in the reduction of a starting compound II, two or three of Y¹, Y²and Y³ represent different halogen atoms, it is the halogen atom ofhighest molecular weight which is removed during the process. Thus, forexample, to prepare a compound of the general formula I, in which bothY¹ and Y² represent bromine atoms, a starting material is used in whichY³ also represents a bromine atom, while to prepare a compound of thegeneral formula I, in which both Y¹ and Y² represent chlorine atoms, astarting material in which Y³ represents either a chlorine or a bromineatom may be used.

The reaction conditions for the reduction process must be such that theacid group in a compound II, where Z represents a hydroxy group, is notreduced, and this depends principally on a suitable choice of selectivereducing agent. For example, lithium aluminium hydride cannot be usedsince it attacks the acid group, but modified alkali metal aluminiumhydrides, such as lithium aluminium (tri-t-butoxy)hydride, may be used.

Suitable reducing agents include those of the following formulae:##STR4## in which M represents an alkali metal, R³ represents an alkylgroup having 1 to 4 carbon atoms, n represents an integer 1 to 4, and mrepresents an integer 1 to 3. Typical reducing agents of this typeinclude lithium borohydride, sodium borohydride, aluminiumtri-isopropoxide, (generally used in the presence of isopropyl alcohol),lithium aluminium (tri-t-butoxy)hydride and sodium dithionite. Sodiumborohydride is especially preferred.

The reaction medium chosen for the reduction depends, of course, on thereducing agent chosen since certain reducing agents will react withprotic solvents. In general, a suitable solvent may be selected fromwater, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, acetonitrile,alcohols, for example, isopropanol, amides, for example,dimethylformamide or dimethylacetamide, and ethers, for example,tetrahydrofuran. Mixtures of solvents may often be useful.

The reduction is preferably conducted at elevated temperature,especially when Y³ represents a chlorine atom. Preferably, the reactiontemperature is at least 50° C., for example, in the range from about 50°C. to about 150° C., especially about 60° C. to about 120° C.

Choice of reaction conditions may have a marked effect on the yield ofthe compound of the general formula I. For instance, if sodiumborohydride is used as reducing agent and water as solvent, and thereaction is carried out at room temperature, the yield of the compoundof the general formula I tends to be low if Y³ represents a chlorineatom, but rather higher if Y³ represents a bromine atom. If, however, anaprotic solvent such as dimethylformamide is used and the reaction isconducted at an elevated temperature, the yield of the compound of thegeneral formula I is increased.

In the preparation of a compound of the formula I from a compound of theformula IIa ##STR5## (wherein in formula II Y³ and X both representhydrogen atoms and W and Z both represent hydroxy groups), suitabledehydrating agents include acids, for example, mineral acids such assulphuric or phosphoric acid, or organic acids, for example, p-toluenesulphonic acid or acetic acid; acid anhydrides, for example, aceticanhydride or phosphoric anhydride; and acid chlorides, for example,phosphorus trichloride, phosphorus oxychloride or acetyl chloride.Phosphorus trichloride and p-toluene sulphonic acid are preferreddehydrating agents.

The dehydrating process is suitably carried out in the presence of aninert solvent, for example, a hydrocarbon or halogenated hydrocarbon,such as benzene, toluene, chloromethane or trichloromethane, an ether,for example, tetrahydrofuran or diethyl ether, N-methylpyrrolidone,acetonitrile or dimethylsulphoxide. The reaction temperature may varywidely depending on the dehydrating agent used, but is preferably in therange of from about 15° C. to about 150° C. Room temperature is oftenconvenient, for example, when using phosphorus trichloride. When usingan acid as dehydrating agent, it is often convenient to carry out thereaction at the reflux temperature of the solvent used, whileazeotropically distilling off water.

A compound of formula II which contains a CY¹ Y² Y³.CO-- group and a--CO₂ H group cis to each other, is the keto tautomer of a lactol offormula II in which Z and X together represent an oxygen atom. Insolution, these keto-lactol tautomers generally co-exist as anequilibrium mixture. Local conditions of temperature, solvent, etc.,determine the relative proportions of the tautomers in the equilibriummixture. These tautomers of formula II can be prepared by the reactionof an anhydride of the general formula III ##STR6## with a trihalocompound of the general formula IV ##STR7## in which Y¹, Y², Y³, R¹ andR² have the meanings given above, and M represents an alkali metal, forexample, sodium or potassium. The reaction is preferably carried out inan inert polar aprotic solvent, for example, acetonitrile. The reactiontemperature may, for example, be in the range of from about -60° C. toabout 60° C.

A compound of formula II in which Y³ represents a chlorine or bromineatom, X represents a hydrogen atom and both of W and Z represent hydroxygroups may be prepared as disclosed in U.S. patent 4,166,063 by reactionof a compound of the formula V ##STR8## with a compound of the formulaVI

    CH.Y.sup.1 Y.sup.2 Y.sup.3                                 (VI)

in which R¹, R², Y¹, Y² and Y³ have the meanings given above. in thepresence of a base. Suitable bases include alkali metal alkoxides,hydrides and hydroxides, and the reaction is preferably carried out inthe presence of an organic solvent, for example an alkanol,dimethylformamide, dimethylsulphoxide, an ether or an aliphatichydrocarbon.

A compound of the general formula II in which Y³ represents a hydrogenatom, may be prepared by reduction of a cis keto acid of the generalformula VII and/or its lactol tautomer of the general formula VIII:##STR9## in which Y¹, Y², R¹ and R² have the meanings given above. usingany suitable reducing agent. Especially suitable reducing agents are thesame preferred metal salts described above, especially alkali metalborohydrides, for example sodium borohydride, and suitable solvents alsoinclude those described above.

The compounds of the formulae VII and VIII exhibit the same type oftautomerism as described above. They can be prepared by catalytichydrogenation of the keto-lactol tautomers of formula II described abovein which Y³ represents a chlorine or bromine atom, W and X togetherrepresent an oxygen atom and Z represents a hydroxy group, in a suitablesolvent. The use of a palladium charcoal catalyst in an alkanoic acidsuch as propionic acid or, especially, acetic acid as reaction medium ispreferred, and the reduction is conveniently carried out at roomtemperature.

A compound of the general formula I can be converted into acorresponding 2,2-dihalovinyl derivative, and the invention thereforealso provides a process for the preparation of a cisdihalovinylcyclopropane carboxylic acid of the general formula IX##STR10## in which Y¹, Y²,R¹ and R² have the meanings given for thegeneral formula I, which comprises reacting a compound of the generalformula I with a base.

The base is suitably a strong base and may for example be an alkalimetal hydroxide, hydride or alkoxide, for example sodium hydroxide orpotassium tertiary butoxide. Alkali metal alkoxides are especiallypreferred. Any suitable solvent, for example dimethylsulphoxide,N-methyl-pyrrolidone, an alcohol, such as methanol, an ether, such astetrahydrofuran, or an amide, such as dimethylacetamide, may be used. Itmay be convenient to use a solvent for the compound of the generalformula I in which the base is insoluble, for example dioxan, and toconduct the reaction using solid base in the presence of aphase-transfer catalyst, for example tetrabutylammonium chloride. Thereaction is suitably carried out at a temperature in the range of fromabout 0° C. to about 100° C. It may be convenient to carry out thereaction at room temperature or at the reflux temperature of the solventused.

By a suitable choice of reaction conditions, it may be convenient toprepare a compound of the general formula I and then, withoutintermediate isolation or workup, to convert it in situ into a compoundof the general formula IX.

If an optically active compound of the general formula I is prepared,for example one having the R configuration at the cyclopropane carbonatom bearing the --CO₂ -- group, reaction with a base normally proceedswith retention of configuration to give the corresponding optical isomerof the compound of the general formula IX. Optically active compounds ofthe general formula I may be prepared by standard methods, for exampleby starting from optically active starting materials or by separatingthe racemic mixture.

EXAMPLES

The following Examples illustrate the invention. All NMR data are givenin units of ppm using tetramethyl silane as standard.

EXAMPLE 1 preparation of cis 2-trichloroacetyl-3,3-dimethylcyclopropanecarboxylic acid and its lactol tautomer

A suspension of sodium trichloroacetate (0.74 g. 4.0 mmol) in 10 mlacetonitrile and caronic anhydride (0.5 g) was stirred for 20 hours atroom temperature. The reaction mixture was then acidified with 0.5 mlconcentrated HCl, diluted with water and extracted with dichloromethane.The extracts were washed with water, dried over magnesium sulphate,filtered and evaporated to dryness. 0.8 g of a white solid wereobtained. A solution of this solid in CDCl₃ was shown by NMR to containa mixture of cis 2-trichloroacetyl-3,3-dimethylcyclopropane carboxylicacid and its lactol tautomer,4-hydroxy-4-trichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one.

EXAMPLE 2 Preparation of cis 2-dichloroacetyl-3,3-dimethylcyclopropanecarboxylic acid and its lactol tautomer

A crude mixture containing 84% of the tautomers described in Example 1and 16% caronic anhydride (4.0 g, prepared by the method of Example 1)was added to 20 ml acetic acid and 100 mg of 10% palladium on charcoal.Hydrogen was bubbled through the stirred mixture for 41/2 hours at roomtemperature. The mixture was then filtered, the solvent was removedunder reduced pressure, 20 ml toluene was added to the residue, and themixture was filtered. The filtrate was evaporated under reduced pessureleaving 2.8 g of an oil. NMR showed that an 80% yield of cis2-dichloroacetyl-3,3-dimethylcyclopropane carboxylic acid and its lactoltautomer,4-hydroxy-4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]-hexan-2-one,had been obtained.

    ______________________________________                                        .sup.13 C NMR results                                                         keto Acid      endo lactol                                                                             exo lactol                                           ______________________________________                                        14.9           17.2      16.8                                                 27.4           25.8      27.9                                                 31.2           26.4      28.3                                                 33.6           31.7      32.2                                                 35.0           34.0      36.2                                                 70.0           74.8      72.0                                                 174.4          104.6     102.9                                                192.6          172.6     174.9                                                ______________________________________                                    

EXAMPLE 3 Preparation of cis2-(1-hydroxy-2,2-dichloroethyl)-3,3-dimethylcyclopropane carboxylic acid

A portion of the crude reaction mixture of Example 2 (9 mmol product)was dissolved in a solution of sodium bicarbonate (10 mmol) in water (10ml) at room temperature, and sodium borohydride (4.5 mmol) was added.After stirring for 11/2 hours at room temperature, the solution wasextracted with chloroform, acidified with concentrated HCl, andextracted again with chloroform. Filtration and evaporation left 1.5 gof an oil which was shown by NMR to contain 90% of the desired product,as a mixture of two diasterioisomers in a ratio approximately 15:1.

    ______________________________________                                        .sup.13 C NMR                                                                        isomer 1                                                                             isomer 2                                                        ______________________________________                                               14.59  15.56                                                                  26.68  28.12                                                                  28.65  28.24                                                                  29.53  28.77                                                                  34.30  35.36                                                                  71.47  72.00                                                                  76.47  75.47                                                                  176.90 177.34                                                          ______________________________________                                    

EXAMPLE 4 Preparation of4-dichloromethyl-6,6-dimethyl-3-oxabicylo[3.1.0]hexan-2-one

Phosphorus trichloride (4.5 mmol) was added to a solution of the crudehydroxy acid prepared as in Example 3 (4.4 mmol) in chloroform (10 ml).After stirring for 1/2 hour at 40° C. and washing with a saturatedsodium bicarbonate solution, the organic phase was dried over magnesiumsulphate, filtered and evaporated under reduced pressure, to give 0.45 gof an oil shown by NMR to contain 76% of the desired product, largely inthe form of endo isomer but with some exo isomer present (approximateratio 15:1).

    ______________________________________                                        .sup.13 C NMR                                                                 endo isomer    exo isomer                                                     ______________________________________                                        17.48          14.97                                                          24.74          23.08                                                          25.73          25.05                                                          30.78          30.37                                                          32.62          30.97                                                          69.09          72.05                                                          83.09          78.73                                                          171.87         172.10                                                         ______________________________________                                    

EXAMPLE 5 Preparation of4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one

Sodium borohydride (0.12 mmol) was added to a solution of cis2-(1-hydroxy-2,2,2-trichloroethyl)-3,3-dimethylcyclopropane carboxylicacid (0.12 mol) in dry dimethylformamide (0.4 ml), and the mixture washeated for 30 minutes at 80° C. An additional amount of 0.12 mmol sodiumborohydride was then added and the mixture was heated for a further 15minutes at 80° C. It was then diluted with water, acidified withconcentrated HCl and extracted with deuterochloroform, CDCl₃. Theextract was washed with water and analysed by NMR, which showed a yieldof 25% of the desired product, with 30% of unconverted startingmaterial.

EXAMPLE 6 Preparation of4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one

Sodium borohydride (0.36 mmol) and the keto/lactol tautomers describedin Example 1 (0.17 mmol) were dissolved in dry dimethylformamide (0.4ml) and heated for 3 hours at 80° C. The reaction mixture was thendiluted with water, acidified with concentrated HCl, and extracted withCDCl₃. The extract was washed with water and analysed by NMR, whichshowed a yield of 28% of the desired compound.

EXAMPLE 7 Preparation of4-dibromomethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one

Cis 2-tribromoacetyl-3,3-dimethylcyclopropane carboxylic acid (0.2 mmol)prepared by a method analogous to that described in Example 1, wasstirred for 10 minutes with a solution of sodium borohydride (0.8 mmol)in 5 ml water at room temperature for 16 hours and the crystallinereaction product was then filtered off and dried under reduced pressureat 40° C. The resulting product weighed 13 mg and contained 50% of thedesired product, largely in the form of the endo isomer.

    ______________________________________                                        Proton NMR in CDCl.sub.3                                                      ______________________________________                                        1.20 (s, 3H)                                                                  1.37 (s, 3H)                                                                  2.23 (m, 2H)                                                                  5.00 (dd, 1H) coupling constants J = 5 Hz                                     J = 10 Hz                                                                     5.72 (d, 1H) J = 10 Hz                                                        ______________________________________                                    

EXAMPLE 8 Preparation of cis2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylic acid

Potassium tertiary butoxide (0.45 mol) was added to a solution of4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]-hexan-2-one (0.16mmol) in dry dimethylsulphoxide (0.4 ml) and stirred at room temperaturefor 1/2 hour. The solution was then diluted with water, acidified withconcentrated hydrochloric acid and extracted CDCl₃. NMR analysis showeda virtually quantitative yield of the desired cis acid.

EXAMPLE 9 Preparation of cis2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylic acid

A solution of 2.5 mmol sodium hydroxide in 5 ml absolute ethanol wasmixed with 4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one(0.1 mmol) and heated for 2 hours at 55° C. The solvent was then removedunder reduced pressure, and the residue was diluted with water,acidified with concentrated hydrochloric acid and extracted with CDCl₃.NMR indicated a yield of 24% of the desired cis acid.

I claim:
 1. A compound of the formula ##STR11## wherein each of Y¹ andY² independently represents a fluorine, chlorine or bromine atom andeach of R¹ and R² independently represents a hydrogen atom or an alkylgroup having up to 10 carbon atoms, or R¹ and R² together represent analkylene group having from 2 to 5 carbon atoms.
 2. A compound accordingto claim 1 wherein each of R¹ and R² independently represents an alkylgroup having 1 to 4 carbon atoms.
 3. A compound according to claim 2wherein both R¹ and R² represent methyl groups.
 4. A compound accordingto claim 3 wherein Y¹ and Y² both represent chlorine atoms or Y¹ and Y₂both represent bromine atoms.